Fluid Complications

June 1, 2007

Malignant pleural effusions complicate the care of approximately 150,000 people in the United States each year. The pleural effusion is usually caused by a disturbance of the normal Starling forces regulating reabsorption of fluid in the pleural space, secondary to obstruction of mediastinal lymph nodes draining the parietal pleura. Tumors that metastasize frequently to these nodes, eg, lung cancer, breast cancer, and lymphoma, cause most malignant effusions. It is, therefore, puzzling that small-cell lung cancer infrequently causes effusions. Primary effusion lymphomas caused by human herpesvirus 8 and perhaps Epstein-Barr virus (EBV) are seen in patients with AIDS.

MALIGNANT PLEURAL EFFUSION

Malignant pleural effusions complicate the care of approximately 150,000 people in the United States each year. The pleural effusion is usually caused by a disturbance of the normal Starling forces regulating reabsorption of fluid in the pleural space, secondary to obstruction of mediastinal lymph nodes draining the parietal pleura. Tumors that metastasize frequently to these nodes, eg, lung cancer, breast cancer, and lymphoma, cause most malignant effusions. It is, therefore, puzzling that small-cell lung cancer infrequently causes effusions. Primary effusion lymphomas caused by human herpesvirus 8 and perhaps Epstein-Barr virus (EBV) are seen in patients with AIDS.

Pleural effusion restricts ventilation and causes progressive shortness of breath by compression of lung tissue as well as paradoxical movement of the inverted diaphragm. Pleural deposits of tumor cause pleuritic pain.

Pleural effusions commonly occur in patients with advanced-stage tumors, who frequently have metastases to brain, bone, and other organs, physiologic deficits, malnutrition, debilitation, and other comorbidities. Because of these numerous clinical and pathologic variables, it is difficult to perform meaningful trials in patients with pleural effusions. For the same reason, it is often difficult to predict a potential treatment outcome for the specific patient with multiple interrelated clinical problems. Altundag and colleagues from M. D. Anderson Cancer Center performed a retrospective study of patients with "wet" IIIB non–small-cell lung cancer. Of the 37 patients who had no detectable distant metastasis at the time of diagnosis, 12 (32%) experienced improved survival. They concluded that selected patients with wet IIIB disease may benefit from aggressive local treatment strategies.

Diagnosis

The new onset of a pleural effusion may herald the presence of a previously undiagnosed malignancy or, more typically, complicate the course of a known tumor.

Thoracentesis The first step in management in almost all cases is thoracentesis. An adequate specimen should be obtained and sent for cell count; determination of glucose, protein, lactic dehydrogenase (LDH), and pH; and appropriate cultures and cytology. A negative cytology result is not uncommon and does not rule out a malignant etiology.

The Light criteria (LDH > 200 U/L; pleural-serum LDH ratio > 0.6, and pleural-serum protein ratio > 0.5) help categorize pleural effusions as exudates. The majority of undiagnosed exudates are eventually diagnosed as malignant, whereas < 5% of transudates are shown to be caused by cancer.

Because it is sometimes difficult to prove the malignant nature of an effusion, many molecular tests on pleural fluid have been investigated. Multiple reports measure pleural tumor marker proteins, cadherins, matrix metalloproteins, cytokines, telomerase, mRNA, exosomes, and serum and pleural DN methylation patterns, but to date, no test or panel of tests can reliably diagnose malignant effusions.

Pleural biopsy If cytology of an exudative effusion is negative and malignant disease is still suspected (approximately 50% of cases), blind pleural biopsy
has a low diagnostic yield that can be improved by CT or ultrasonographic guidance.

Thoracoscopy Thoracoscopic examination is emerging as a reliable diagnostic technique with a low complication rate. It allows comprehensive visualization of one pleural cavity, coupled with the opportunity to biopsy areas of disease. This method provides a definitive diagnosis and allows the pathologist to suggest possible sites of primary disease based on the histopathology. Furthermore, this technique permits the diagnosis and staging of malignant mesothelioma if it is the cause of the effusion. Thoracoscopy also offers the opportunity for simultaneous treatment.

Bronchoscopy may be helpful when an underlying lung cancer is suspected, especially if there is associated hemoptysis, a lung mass, atelectasis, or a massive effusion. It may also be useful when there is a cytologically positive effusion with no obvious primary tumor.

Prognosis

Prognosis of patients with malignant pleural effusion varies by primary tumor. For example, median survival for patients with lung cancer is 3 months, whereas it is 10 months for patients with breast cancer. Median survival is also shorter in patients with encasement atelectasis (3 months).

Treatment

INITIAL TREATMENT
Because the specific clinical circumstances may vary markedly in different patients, treatment must be individualized to provide the best palliation for each patient. In general, malignant pleural effusion should be treated aggressively as soon as it is diagnosed. In most cases, effusion will rapidly recur after treatment by thoracentesis or tube thoracostomy alone. If the clinician decides to administer systemic chemotherapy for the underlying primary malignancy, in tumors such as breast cancer, lymphoma, and small-cell lung cancer, it is important to monitor the patient carefully for recurrent effusion and treat such recurrences immediately.

If a malignant pleural effusion is left untreated, the underlying collapsed lung will become encased by tumor and fibrous tissue in as many as 10%–30% of cases. Once this encasement atelectasis has occurred, the underlying lung is "trapped" and will no longer reexpand after thoracentesis or tube thoracostomy. Characteristically, the chest x-ray in such cases shows resolution of the pleural effusion after thoracentesis, but the underlying lung remains partially collapsed. This finding is often misinterpreted by the inexperienced clinician as evidence of a pneumothorax, and a chest tube is placed. The air space persists and the lung remains unexpanded, even with high suction and pulmonary physiotherapy. Allowing the chest tube to remain in place can worsen the situation, resulting in bronchopleural fistulization and empyema.

Physical techniques

To avoid encasement atelectasis, pleural effusion should be treated definitively at the time of initial diagnosis. Multiple physical techniques of producing adhesions between the parietal and visceral pleurae, obliterating the space, and preventing recurrence have been used. They include open or thoracoscopic pleurectomy, gauze abrasion, or laser pleurodesis. Surgical methods have not been demonstrated to have any advantage over simpler chemical pleurodesis techniques in the treatment of malignant effusions. Gauze abrasion can easily be employed when unresectable lung cancer with associated effusion is found at the time of thoracotomy.

A randomized, prospective study from Ljubljanska, Slovenia, of 87 patients with malignant pleural effusion secondary to breast cancer showed that the thoracoscopic mechanical abrasion pleurodesis was equivalent to talc pleurodesis in those with normal pleural fluid pH and superior in patients with a low pH.

Chemical agents

Multiple chemical agents have been used.

Tetracycline Tetracycline pleurodesis results in a lower incidence of recurrence when compared with tube thoracostomy alone but often causes severe pain.

Doxycycline and minocycline are probably equivalent in efficacy to tetracycline.

Bleomycin Intrapleural bleomycin, in a dose of 60 U, has been shown to be more effective than tetracycline and is not painful, but it is costly. Absorption of the drug can result in systemic toxicity. Combined use of tetracycline and bleomycin has been demonstrated to be more efficacious than the use of either drug singly.

 

Talc pleurodesis was first introduced by Bethune in the 1930s. Talc powder (Sclerosol Intrapleural Aerosol) has demonstrated efficacy in numerous large studies, preventing recurrent effusion in 70%–92% of cases. Talc is less painful than tetracycline. Cost is minimal, but special sterilization techniques must be mastered by the hospital pharmacy. Talc formulations may have significant differences in the size of particles. Smaller particles may be absorbed and disseminated systemically.

Talc can be insufflated in a dry state at the time of thoracoscopy or instilled as a slurry through a chest tube. The dose should be restricted to no more than 5 g. A prospective phase III intergroup trial of 501patients randomized to receive thoracoscopic talc vs talc slurry pleurodesis showed similar efficacy in each arm, with increased respiratory complications (14% vs 6%) but less fatigue and higher patient ratings in the insufflation group.

Multiloculated effusions may follow talc use. It is important to ensure that talc does not solidify and form a concretion in the chest tube, thus preventing the drainage of pleural fluid and complete reexpansion of the lung following pleurodesis. Such an event is more likely when small-bore chest tubes are used.

Pleurodesis technique With talc pleurodesis, a 24- to 32-French tube has customarily been inserted through a lower intercostal space and placed on underwater seal suction drainage until all fluid is drained and the lung has completely reexpanded. Because severe lung damage can be produced by improper chest tube placement, it is imperative to prove the presence of free fluid by a preliminary needle tap and to enter the pleural space gently with a blunt clamp technique, rather than by blind trocar insertion. If there is any question about the presence of loculated effusion or underlying adhesions, the use of CT or sonography may enhance the safety of the procedure. In the case of large effusions, especially those that have been present for some time, the fluid should be drained slowly to avoid reexpansion pulmonary edema.

Significant complications can occur with both thoracentesis and chest tube thoracostomy. These procedures should not be performed by inexperienced practitioners without training and supervision.

Premedications If doxycycline or talc is to be used, the patient should be premedicated with narcotics. Intrapleural instillation of 20 mL of 1% lidocaine before administration of the chemical agent may help reduce pain.

Following instillation of the chemical agent, the chest tube should remain clamped for at least 2 hours. If high-volume drainage persists, the treatment can be repeated. The chest tube can be removed after 2 or 3 days if drainage is < 300 mL/day.

Follow-up x-rays at monthly intervals assess the adequacy of treatment and allow early retreatment in case of recurrence.

Alternative approaches Use of fluid-sclerosing agents and outpatient pleurodesis has been advocated by some investigators and has the potential for reducing hospital stay and treatment cost. Patz performed a prospective, randomized trial of bleomycin vs doxycycline (72% bleomycin vs 79% doxycycline) pleurodesis via a 14-French catheter and found no difference in efficacy.

Other approaches that must be considered experimental at this time include quinacrine, iodopovidone, and silver nitrate and use of various biologic agents, including Corynebacterium parvum, OK-432, tumor necrosis factor, interleukin-2 (Proleukin), interferon-α (Intron A, Roferon-A), interferon-β (Betaseron), and interferon-γ (Actimmune).

TREATMENT OF ENCASEMENT ATELECTASIS

If encasement atelectasis is found at thoracentesis or thoracoscopy, tube thoracostomy and pleurodesis are futile and contraindicated.

Surgical decortication has been advocated for this problem. This potentially dangerous procedure may result in severe complications, however, such as bronchopleural fistula and empyema.

Pleuroperitoneal shunts The Royal Brompton Hospital, London, group reported experience with pleuroperitoneal shunts in 160 patients with malignant pleural effusion and a trapped lung. Effective palliation was achieved in 95% of patients; 15% of patients required shunt revisions for complications.

Intermittent thoracentesis, as needed to relieve symptoms, may be the best option in patients with a short anticipated survival.

Catheter drainage Another new option is to insert a tunneled, small-bore, cuffed, silicone catheter (PleurX pleural catheter, Denver Biomaterials, Inc., Denver, Colorado) into the pleural cavity. The patient or family members may then drain fluid, using vacuum bottles, whenever recurrent effusion causes symptoms.

Kakuda reported on placement of 61 PleurX pleural catheters in 50 patients with malignant pleural effusions at City of Hope. Thirty-four percent had lung cancer and 24% had breast cancer. There were no operative deaths. In cases where the catheter was placed under thoracoscopic control, 27 of 38 patients (68%) had encasement atelectasis visualized. Eighty-one percent had a good result with control of effusion, with subsequent catheter removal (19%) or intermittent drainage for > 1 month or until death (62%). Five percent of patients had major complications, including empyema and tumor implant.

Putnam prospectively compared PleurX catheter drainage with doxycycline pleurodesis and found the two to be equally effective.

Chemotherapy options depend on the cell type of the tumor and the general condition of the patient. Although intrapleural chemotherapy offers the possibility of high-dose local therapy with minimal systemic effects, only a few, small pilot studies utilizing mitoxantrone (Novantrone), doxorubicin, and hyperthermic cisplatin have been published.

Ang and colleagues from Singapore reported longer mean survival (12 vs 5 months) when systemic chemotherapy was given to 71 patients who initially presented with malignant pleural/pericardial effusions. New studies in this area are much needed.

In Taiwan, Su et al treated 27 patients with non–small-cell lung cancer presenting with a malignant pleural effusion with a regimen of intrapleural cisplatin and gemcitabine, followed by radiotherapy (7,020 cGy in 39 fractions), and completed with IV docetaxel. Only two patients experienced recurrent pleural effusion. The median disease-free and overall survival rates were 8 and 16 months, respectively, and 63% of patients were alive at 1 year.

Radiation therapy may be indicated in some patients with lymphoma but has limited effectiveness in other tumor types, particularly if mediastinal adenopathy is absent.

Chylothorax (in the absence of trauma) is usually secondary to cancer, most frequently lymphoma. An added element of morbidity is conferred by the loss of protein, calories, and lymphocytes in the draining fluid. Chylothorax secondary to lymphoma is usually of low volume and responds to talc pleurodesis in combination with radiotherapy or chemotherapy.

PERICARDIAL EFFUSION

Pericardial effusion develops in 5%–15% of patients with cancer and is sometimes the initial manifestation of malignancy. Most pericardial effusions in cancer patients result from obstruction of the lymphatic drainage of the heart secondary to metastases. The typical presentation is that of a patient with known cancer who is found to have a large pericardial effusion without signs of inflammation. Bloody pericardial fluid is not a reliable sign of malignant effusion.

The most common malignant causes of pericardial effusions are lung and breast cancers, leukemias (specifically acute myelogenous, lymphoblastic, and chronic myelogenous leukemia [blast crisis]), and lymphomas.

Not all pericardial effusions associated with cancer are malignant, and cases with negative cytology may represent as many as half of cancer-associated pericardial effusions. Such effusions are more common in patients with mediastinal lymphoma, Hodgkin lymphoma, or breast cancer. Other nonmalignant causes include drug-induced or postirradiation pericarditis, tuberculosis, collagen diseases, uremia, and congestive heart failure. Many effusions that initially have negative cytology will become positive over time.

Tamponade occurs when fluid accumulates faster than the pericardium can stretch. Compression of all four heart chambers ensues, with tachycardia and diminishing cardiac output. Fluid loading can counteract intrapericardial pressure temporarily. Reciprocal filling of right- and left-sided chambers with inspiration and expiration, secondary to paradoxical movement of the ventricular septum, is a final mechanism to maintain blood flow before death.

Diagnosis

A high index of suspicion is required to make the diagnosis of pericardial effusion.

Signs and symptoms Dyspnea is the most common symptom. Patients may also complain of chest pain or discomfort, easy fatigability, cough, and orthopnea or may be completely asymptomatic. Signs include distant heart sounds and pericardial friction rub. With cardiac tamponade, progressive heart failure occurs, with increased shortness of breath, cold sweats, confusion, pulsus paradoxus > 13 mm Hg, jugular venous distention, and hypotension.

Chest x-ray Chest radiographic evidence of pericardial effusion includes cardiomegaly with a "water bottle" heart; an irregular, nodular contour of the cardiac shadow; and mediastinal widening.

ECG The ECG shows nonspecific ST- and T-wave changes, tachycardia, low QRS voltage, electrical alternans, and atrial dysrhythmia.

Pericardiocentesis and echocardiography An echocardiogram not only can confirm a suspected pericardial effusion but also can document the size of the effusion and its effect on ventricular function. A pericardial tap with cytologic examination (positive in 50%–85% of cases with associated malignancy) will confirm the diagnosis of malignant effusion or differentiate it from other causes of pericardial effusion. Serious complications, including cardiac perforation and death, can occur during pericardiocentesis, even when performed with echocardiographic guidance by experienced clinicians.

Tumor markers or special staining and cytogenetic techniques may improve the diagnostic yield, but ultimately an open pericardial biopsy may be necessary. Szturmowicz from Warsaw, Poland, studied pericardial fluid carcinoembryonic antigen (CEA) and CYFRA 21-1 levels in 84 patients with pericardial effusion. There were significant differences in patients with malignant vs benign effusions with both tests. Using cutoff points of > 100 ng/mL for CYFRA 21-1 and > 5 ng/mL for CEA, 14 of 15 patients with malignant pericardial effusion with negative cytologic results had a positive result on one or both tests.

CT and MRI as diagnostic adjuncts may provide additional information about the presence and location of loculations or mass lesions within the pericardium and adjacent structures.

Cardiac catheterization may occasionally be of value to rule out superior vena caval obstruction, diagnose microvascular tumor spread in the lungs with secondary pulmonary hypertension, and document constrictive pericarditis before surgical intervention. Pericardial fluid has been aspirated in experimental animals by femoral vein catheterization and needle puncture of the right atrial appendage from within. This technique has not been used in humans.

Pericardioscopy allows visualization and biopsy at the time of subxiphoid or thoracoscopic pericardiotomy and can improve the diagnostic yield.

Prognosis

In general, cancer patients who develop a significant pericardial effusion have a high mortality, with a mean time to death of 2.2–4.7 months. However, about 25% of selected patients treated surgically for cardiac tamponade enjoy a 1-year survival.

Treatment

General concepts

As is the case with malignant pleural effusion, it is difficult to evaluate treatments for pericardial effusion because of the many variables. Since malignant pericardial effusion is less common than malignant pleural effusion, it is more difficult to collect data in a prospective manner. Certain generalizations can, however, be derived from available data:

  • All cancer patients with pericardial effusion require a systematic evaluation and should not be dismissed summarily as having an untreatable and/or terminal problem.

  • Ultimately, both the management and natural course of the effusion depend on (1) the underlying condition of the patient, (2) the extent of clinical symptoms associated with the cardiac compression, and (3) the type and extent of the underlying malignant disease.

 

GENERAL TREATMENT APPROACHES

Asymptomatic, small effusions may be managed with careful follow-up and treatment directed against the underlying malignancy. On the other hand, cardiac tamponade is a true oncologic emergency. Immediate pericardiocentesis, under echocardiographic guidance, may be performed to relieve the patient's symptoms. A high failure rate is anticipated because the effusion rapidly recurs unless steps are taken to prevent it. Therefore, a more definitive treatment plan should be made following the initial diagnostic/therapeutic tap.

In patients with symptomatic, moderate-to-large effusions who do not present as an emergency, therapy should be aimed at relieving symptoms and preventing recurrence of tamponade or constrictive pericardial disease. Patients with tumors responsive to chemotherapy or radiation therapy may attain longer remissions with appropriate therapy.

There are two theoretical mechanisms for control of pericardial effusion: creation of a persistent defect in the pericardium allowing fluid to drain out and be reabsorbed by surrounding tissues or sclerosis of the mesothelium resulting in the formation of fibrous adhesions that obliterate the pericardial cavity.

Postmortem studies have demonstrated that both of these mechanisms are operative. The fact that effusions can recur implies that there is either insufficient damage to the mesothelial layer or that rapid recurrence of effusion prevents coaptation of visceral and parietal pericardium and prevents the formation of adhesions. This, in turn, would suggest that early closure of the pericardial defect can result in recurrence.

TREATMENT METHODS

Various methods can be used to treat malignant pericardial effusion.

Observation Observation alone may be reasonable in the presence of small asymptomatic effusions.

Pericardiocentesis is useful in relieving tamponade and obtaining a diagnosis. Echocardiographic guidance considerably enhances the safety of this procedure. Ninety percent of pericardial effusions will recur within 3 months after pericardiocentesis alone.

Pericardiocentesis and percutaneous tube drainage can now be performed with low risk and are recommended by some clinical groups. Problems that may occur include occlusion or displacement of the small-bore tubes, dysrhythmia, recurrent effusion, and infections. Mayo Clinic cardiologists recommend initial percutaneous pericardiocentesis with extended catheter drainage as their technique of choice.

Intrapericardial sclerotherapy and chemotherapy following percutaneous or open drainage have been reported to be effective treatments by some groups. Problems include pain during sclerosing agent treatments and recurrence of effusions. Good results have been reported with instillation of a number of agents, including bleomycin (10 mg), cisplatin (30 mg), mitomycin C (2 mg), thiotepa (1.5 mg), and mitoxantrone (10–20 mg). Agents are selected based on their antitumor or sclerosing effect.

Pericardiocentesis and balloon pericardial window After percutaneous placement of a guidewire following pericardiocentesis, a balloon dilating catheter can be placed across the pericardium under fluoroscopic guidance and a window created by balloon inflation.

At the National Taiwan University, cardiologists performed percutaneous double-balloon pericardiotomy in 50 patients with cancer and pericardial effusion and followed their course using serial echocardiograms. Success without recurrence was achieved in 88%. Fifty percent of patients died within 4 months, and 25% survived to 11 months.

Subtotal pericardial resection is seldom performed today. Although it is the definitive treatment, in that there is almost no chance of recurrence or constriction, higher morbidity and longer recovery time render this operation undesirable in patients who have a short anticipated survival. Its use is restricted to cancer patients with recurrent effusions who are in good overall condition and are expected to survive for up to 1 year.

Limited pericardial resection (pericardial window) via anterior thoracotomy or a thoracoscopic approach has a lower morbidity than less invasive techniques, but recovery is delayed. There is a low risk of recurrence. Cardiac herniation is possible if the size of the opening in the pericardium is not carefully controlled.

Subxiphoid pericardial resection can be performed with the patient under local anesthesia and may be combined with tube drainage and/or pericardial sclerosis. Our group and others have noted recurrences following this technique.

Subxiphoid pericardioperitoneal window through the fused portion of the diaphragm and pericardium has been developed to allow continued drainage of pericardial fluid into the peritoneum. Experience with the procedure is limited, but recurrences may be less frequent than those associated with subxiphoid drainage alone.

Technical factors Prior pleurodesis for malignant pleural effusion makes an ipsilateral transpleural operation difficult or impossible. In lung cancer patients, major airway obstruction may preclude single-lung anesthesia and, thus, thoracoscopic pericardiectomy. Prior median sternotomy may prohibit the use of a subxiphoid approach.

Complications A 30-day mortality rate of 10% or higher has been reported for all of these modalities but is related more to the gravity of the underlying tumor and its sequelae. A small percentage of patients will develop severe problems with pulmonary edema or cardiogenic shock following pericardial decompression. The mechanisms of these problems are poorly understood. Late neoplastic pericardial constriction can occur following initially successful partial pericardiectomy.

Radiotherapy

External-beam irradiation is utilized infrequently in this clinical setting but may be an important option in specialized circumstances, especially in patients with radiosensitive tumors who have not received prior radiation therapy. Responses ranging from 66% to 93% have been reported with this form of treatment, depending on the type of associated tumor.

Systemic therapy

Chemotherapy Systemic chemotherapy is effective in treating pericardial effusions in patients with lymphomas, hematologic malignancies, or breast cancer. Long-term survival can be attained in these patients. If the pericardial effusion is small and/or asymptomatic, invasive treatment may be omitted in some of these cases. Data regarding the effectiveness of systemic chemotherapy or chemotherapy delivered locally in prevention of recurrent pericardial and pleural effusion are limited. New studies in this area are badly needed.

Biologic therapy with various agents is in the early stages of investigation.

MALIGNANT ASCITES

Malignant ascites results when there is an imbalance in the secretion of proteins and cells into the peritoneal cavity and absorption of fluids via the lymphatic system. Greater capillary permeability as a result of the release of cytokines by malignant cells increases the protein concentration in the peritoneal fluid. Recently, several studies have demonstrated higher levels of vascular endothelial growth factor (VEGF), a cytokine known to cause capillary leak, in the sera and effusions of patients with malignancies.

Signs and symptoms

Patients with malignant ascites usually present with anorexia, nausea, respiratory compromise, and immobility. Complaints of abdominal bloating, heaviness, and ill-fitting clothes are common. Weight gain despite muscle wasting is a prominent sign.

Diagnosis

A malignant etiology accounts for only 10% of all cases of ascites. Nonmalignant diseases causing ascites include liver failure, congestive heart failure, and occlusion of the inferior vena cava or hepatic vein. About one-third of all patients with malignancies will develop ascites. Malignant ascites has been described with many tumor types but is most commonly seen with gynecologic neoplasms (~50%), GI malignancies (20%–25%), and breast cancer (10%–18%). In 15%–30% of patients, the ascites is associated with diffuse carcinomatosis of the peritoneal cavity.

Physical examination does not distinguish whether ascites is due to malignant or benign conditions. Patients may have abdominal fullness with fluid wave, anterior distribution of the normal abdominal tympany, and pedal edema. Occasionally, the hepatic metastases or tumor nodules studding the peritoneal surface can be palpated through the abdominal wall, which has been altered by ascitic distention.

Radiologic studies

Radiographs Ascites can be inferred from plain radiographs of the abdomen. Signs include a ground-glass pattern and centralization of the intestines and abdominal contents.

Ultrasonography Abdominal ultrasonography has been shown to be the most sensitive, most specific method for detecting and quantifying ascites. It also permits delineation of areas of loculation.

CT Abdominal and pelvic CT is effective in detecting ascites. In addition, CT scans may demonstrate masses, mesenteric stranding, omental studding, and diffuse carcinomatosis. Intravenous and oral contrasts are necessary, thus increasing the degree of invasiveness of this modality.

Paracentesis After the diagnosis of peritoneal ascites has been made on the basis of the physical examination and imaging, paracentesis should be performed to characterize the fluid. The color and nature of the fluid often suggest the diagnosis. Malignant ascites can be bloody, opaque, chylous, or serous. Benign ascites is usually serous and clear.

Analysis of the fluid should include cell count, cytology, LDH level, proteins, and appropriate evaluation for infectious etiologies. In addition, the fluid can be sent for the determination of tumor markers, such as CEA, CA-125, p53, and human chorionic gonadotropin-β (hCG-β). The hCG-β level is frequently elevated in malignancy-related ascites and has been combined with cytology to yield an 89.5% efficiency in diagnosis. The use of DNA ploidy indices allowed a 98.5% sensitivity and a 100% sensitivity in the identification of malignant cells within ascitic fluid. The use of the telomerase assay, along with cytologic evaluation of the ascitic fluid contents, has a 77% sensitivity in detecting malignant ascites.

Laparoscopy Several studies have utilized minimally invasive laparoscopy as the diagnostic tool of choice. The fluid can be drained under direct visualization, the peritoneal cavity can be evaluated carefully, and any suspicious masses can be biopsied at the time of the laparoscopy.

Prognosis

The presence of ascites in a patient with malignancy often portends end-stage disease. Median survival after the diagnosis of malignant ascites ranges from 7 to 13 weeks. Patients with gynecologic and breast malignancies have a better overall prognosis than patients with GI malignancies.

Treatment

Medical therapy

Traditionally, the first line of treatment is medical management. Medical therapies include repeated paracentesis, fluid restriction, diuretics, chemotherapy, and intraperitoneal sclerosis.

Repeated paracentesis, probably the most frequently employed treatment modality, provides significant symptomatic relief in the majority of cases. The procedure is minimally invasive and can be combined with abdominal ultrasonography to better localize fluid collections. High-volume paracentesis has been performed without inducing significant hemodynamic instability and with good patient tolerance.

Significant morbidity occurs with repeated taps and becomes more severe with each tap necessary to alleviate symptoms. Ascitic fluid contains a high concentration of proteins. Routine removal of ascites further depletes protein stores. The removal of large volumes of fluid also can result in electrolyte abnormalities and hypovolemia. In addition, complications can result from the procedure itself. They include hemorrhage, injury to intra-abdominal structures, peritonitis, and bowel obstruction. Contraindications to repeated paracentesis are viscous loculated fluid and hemorrhagic fluid.

With the placement of an intraperitoneal port, used also for the instillation of intraperitoneal chemotherapy, removal of ascitic fluid is possible without the need for repeated paracentesis. Other possible catheters for use in repeated paracentesis include PleurX and Tenckoff catheters (used for intraperitoneal dialysis). Placement of a semipermanent catheter minimizes the risk of injury to intra-abdominal structures. However, the benefits are tempered by increased infectious risks as well as the possibility of a nonfunctioning catheter requiring removal and replacement.

Diuretics, fluid and salt restriction Unlike ascites from benign causes such as cirrhosis and congestive heart failure, malignant ascites responds poorly to fluid restriction, decreased salt intake, and diuretic therapy. The most commonly used diuretics (in patients who may have some response to diuretic treatment) are spironolactone (Aldactone) and amiloride (Midamor). Patients with massive hepatic metastases are most likely to benefit from spironolactone.

The onset of action for spironolactone is delayed (3–4 days), whereas the effects of amiloride are seen after 24 hours. The most common complications associated with these diuretics are painful gynecomastia, renal tubular acidosis, and hyperkalemia.

Chemotherapy, both systemic and intraperitoneal, has had some success in the treatment of malignant ascites. The most commonly used agents are cisplatin and mitomycin (Mutamycin). Intraperitoneal hyperthermic chemotherapy has been used with some efficacy in GI malignancies to decrease recurrence of ascites as well as to prevent the formation of ascites in patients with peritoneal carcinomatosis.

Sclerotherapy Sclerosing agents include bleomycin (60 mg/50 mL of normal saline), tetracycline (500 mg/50 mL of normal saline), and talc (5 g/50 mL of normal saline). Responses are seen in ~30% of patients treated with these agents.

Theoretically, intraperitoneal chemotherapy and sclerosis obliterate the peritoneal space and prevent future fluid accumulation. If sclerosis is unsuccessful, it may produce loculations and make subsequent paracentesis difficult.

Other systemic therapies There are several reports of the use of gold-198 or phosphorus-32 in patients with peritoneal effusions, with response rates of 30%–50%. Experimental models and early clinical trials have shown that an intraperitoneal bolus of tumor necrosis factor (45–350 µg/m2) given weekly may be effective in resolving malignant ascites. Other cytokines, including interferon-α, had varying success. A randomized, prospective trial definitively addressing the role of cytokines and other biologic treatments in the management of malignant ascites has yet to be completed.

Surgery

Limited surgical options are available to treat patients who have refractory ascites after maximal medical management, demonstrate a significant decrease in quality of life as a result of ascites, and have a life expectancy of > 3 months.

Peritoneovenous shunts have been used since 1974 for the relief of ascites associated with benign conditions. In the 1980s, shunting was applied to the treatment of malignant ascites.

The LeVeen shunt contains a disc valve in a firm polypropylene casing, whereas the Denver shunt has a valve that lies within a fluid-filled, compressible silicone chamber. Both valves provide a connection between the peritoneal cavity and venous system that permits the free flow of fluid from the peritoneal cavity when a 2- to 4-cm water pressure gradient exists.

Success rates vary with shunting, depending on the nature of the ascites and the pathology of the primary tumor. Patients with ovarian cancer, for example, do very well, with palliation achieved in ≥ 50% of cases. However, ascites arising from GI malignancies is associated with a poorer response rate (10%–15%).

Patient selection Candidates for shunt placement should be carefully selected. Cardiac and respiratory evaluations should be performed prior to the procedure. Shunt placement is contraindicated in the presence of the following:

  • a moribund patient whose death is anticipated within weeks

  • peritonitis

  • major organ failure

  • adhesive loculation

  • thick, tenacious fluid.

Complications of shunting Initial concerns about the use of a shunt in the treatment of malignant ascites centered around intravascular dissemination of tumor. In practice, there has been little difference in overall mortality in patients with and without shunts.

Disseminated intravascular coagulation During the early experience with shunting, particularly in cirrhotic patients, symptomatic clinical disseminated intravascular coagulation (DIC) developed rapidly and was a major source of morbidity and mortality. However, overwhelming DIC occurs infrequently in the oncologic population.

The pathophysiology of DIC has been studied extensively and is thought to be multifactorial. The reinfusion of large volumes of ascitic fluid may cause a deficiency in endogenous circulating coagulation factors by dilution. Secondarily, a fibrinolytic state is initiated by the introduction of soluble collagen (contained within the ascitic fluid) into the bloodstream, leading to a DIC state. Infrequently, full-blown DIC results and requires ligation of the shunt or even shunt removal. Discarding 50%–70% of the ascitic fluid before establishing the peritoneovenous connection may prevent this complication but may increase the risk of early failure due to a reduced initial flow rate.

Commonly, coagulation parameters are abnormal without signs or symptoms. In some institutions, these laboratory values are so consistently abnormal that they are used to monitor shunt patency. Abnormalities most commonly seen include decreased platelets and fibrinogen and elevated prothrombin time, partial thromboplastin time, and fibrin split products.

Other common complications include shunt occlusion (10%–20%), heart failure (6%), ascitic leak from the insertion site (4%), infection (< 5%), and perioperative death (10%–20% when all operative candidates are included).

Shunt patency may be indirectly correlated with the presence of malignant cells. One study found that patients with positive cytology results had a 26-day shunt survival, as compared with 140 days in patients with negative cytology results. Other studies have failed to demonstrate a correlation between ascites with malignant cells and decreased survival.

Clearly, shunting is not a benign procedure, but in carefully selected patients who have not responded to other treatment modalities and who are experiencing symptoms from ascites, it may provide needed palliation. Because of the limited effectiveness of peritoneovenous shunts, patients should be carefully selected prior to shunt placement.

Radical peritoniectomy Other surgical procedures used to treat malignant ascites have been proposed. They include radical peritoniectomy combined with intraperitoneal chemotherapy. This is an extensive operation with significant morbidity, although initial results appear to demonstrate that it decreases the production of ascites. To date, no randomized trial has demonstrated that radical peritoniectomy increases efficacy or survival.

SUGGESTED READING

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ON PERICARDIAL EFFUSIONDosios T, Theakos N, Angouras D, et al: Risk factors affecting the survival of patients with pericardial effusion submitted to subxiphoid pericardiostomy. Chest 124:242–246, 2003.

Maisch B, Seferovic PM, Ristic AD, et al: Guidelines on the diagnosis and management of pericardial diseases executive summary: The Task Force on the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology. Eur Heart J 25:587–610, 2004.

McDonald JM, Meyers BF, Guthrie TJ, et al: Comparison of open subxiphoid pericardial drainage with percutaneous catheter drainage for symptomatic pericardial effusion. Ann Thorac Surg 76:811–816, 2003.

Szturmowicz M, Tomkowksi W, Fijalkowska A, et al: Diagnostic utility of CYFRA 21-1 and CEA assays in pericardial fluid for the recognition of neoplastic pericarditis. Int J Biol Markers 20:43–49, 2005.

Tomkowski WZ, Wisniewska J, Szturmowicz M, et al: Evaluation of intrapericardial cisplatin administration in cases with recurrent malignant pericardial effusion and cardiac tamponade. Support Care Cancer 12:53–57, 2004.

Tsang TS, Enrique-Sarano M, Freeman WK, et al: Consecutive 1,127 therapeutic echocardiographically guided pericardiocenteses: Clinical profile, practice patterns, and outcomes spanning 21 years. Mayo Clin Proc 77:429–436, 2002.

 

ON MALIGNANT ASCITESBecker G, Galandi D, Blum HE: Malignant ascites: Systematic review and guideline for treatment. Eur J Cancer 42:589–597, 2006.

Bieligk SC, Calvo BF, Coit DG: Peritoneovenous shunting for nongynecologic malignant ascites. Cancer 91:1247–1255, 2001.

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